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Nat. Chem. Biol., 04 August 2026 | https://doi.org/10.1038/s41589-026-02278-y Emerging tools to investigate the contribution of selenium to ferroptosis and beyond

Gholamreza Fazeli^1,8, Ihyeon Ahn^2,3,4,8, Michael D. Pluth⁵, Raphael E. F. de Paiva⁶, Namgyu Lee^2,3,4* & José Pedro Friedmann Angeli^1,7*

¹Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
²Department of Biomedical Sciences and Biosystem, Dankook University, Cheonan, Republic of Korea.
³Smart Animal Bio Institute, Dankook University, Cheonan, Republic of Korea.
⁴Korea Institute of Molecular Medicine and Nutrition, Korea University College of Medicine, Seoul, Republic of Korea.
⁵Department of Chemistry and Biochemistry, Materials Science Institute, Knight Campus for Accelerating Scientific Impact, and Institute of Molecular Biology, University of Oregon, Eugene, OR, USA.
⁶Departament de Química, Unitat de Química Inorgànica, Facultat de Ciències, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain.
⁷Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany.
⁸These authors contributed equally: Gholamreza Fazeli, Ihyeon Ahn.

Corresponding authors
Correspondence to Namgyu Lee or José Pedro Friedmann Angeli.

Abstract

Selenium has a paradoxical role in biology, being essential at trace levels yet toxic at slightly higher doses. To operate within this narrow range, organisms have developed specialized pathways for selenium uptake, transport and usage/storage, primarily through selenoprotein biosynthesis. This Review summarizes current understanding of selenium handling and selenoprotein production, and discusses how selenium metabolism shapes susceptibility to ferroptotic cell death. We highlight both the role of selenoproteins in cellular defense and the unexpected roles of small-molecule metabolites, such as hydrogen selenide. We further discuss recent progress in analytical and chemical approaches, including mass spectrometry, activity-based probes and synthetic selenium donors, which are beginning to enable direct interrogation of these transient species. Together, these developments position selenium metabolism as a dynamic, chemically tractable regulator of redox biology and a promising therapeutic target.

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